N Engl J Med. 2021 Aug 26;385(9):815-825. doi: 10.1056/NEJMoa2100665.

ABSTRACT

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear.

METHODS: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group.

RESULTS: After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group.

CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del-gating or Phe508del-residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).

PMID:34437784 | DOI:10.1056/NEJMoa2100665

R I Med J (2013). 2021 Sep 1;104(7):20-25.

NO ABSTRACT

PMID:34437661

Ann Am Thorac Soc. 2021 Aug 26. doi: 10.1513/AnnalsATS.202101-057OC. Online ahead of print.

ABSTRACT

RATIONALE: Elexacaftor/tezacaftor/ivacaftor (ETI) in triple combination improves pulmonary health for people with cystic fibrosis (PwCF) however its impact on objective measures of sinus disease and health utility is unestablished.

OBJECTIVES: To evaluate the impact of ETI on chronic rhinosinusitis (CRS) and general health status incorporating computed tomography (CT), quality-of-life (QOL) and productivity loss.

METHODS: Adult PwCF+CRS with CF transmembrane conductance regulator genotype F508del/F508del or F508del/minimal function who clinically initiated ETI participated in a prospective, observational study. The primary endpoint was change in percent sinus CT opacification (%SO) after 6 months of ETI assessed via deep learning-based methods. Secondary endpoints included changes in sinonasal QOL, health utility value and productivity loss, which were evaluated monthly via validated metrics.

RESULTS: 30 PwCF provided baseline data; 25 completed the study. At baseline, the cohort had substantial CRS, with mean 22-question SinoNasal Outcome Test (SNOT-22) score 33.1 and mean sinus CT %SO 63.7%. At 6-month follow-up, %SO improved by mean 22.9% (p<0.001). %SO improvement trended toward greater magnitude for those naïve to prior modulator therapy (p=0.09). Mean SNOT-22 scores and health utility improved by 15.3 and 0.068 [6.8%] (all p<0.007). Presenteeism, activity impairment and overall productivity loss improved (all p<0.049). Improvements in SNOT-22 scores and health utility occurred by one month and remained improved over the study.

CONCLUSIONS: ETI is associated with substantial improvements in sinus CT opacification and productivity loss, and clinically meaningful improvements in sinonasal QOL and health utility. Most improvements were rapid, robust and durable over the study.

PMID:34436985 | DOI:10.1513/AnnalsATS.202101-057OC

Pediatr Pulmonol. 2021 Aug 26. doi: 10.1002/ppul.25646. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic pulmonary infection is the leading cause of mortality and morbidity in patients with cystic fibrosis (CF). The most common pathogens isolated in CF are Staphylococcus aureus and Pseudomonas aeruginosa (PA). Chronic infection of PA and MRSA are associated with worse survival and antibiotic eradication treatment is recommended for both. This study compared the outcomes between intravenous (IV) and non-IV antibiotics in eradication of PA and MRSA.

METHODS: This was a single-center retrospective study. All respiratory specimen cultures of 309 CF patients and eradication regimens between 2015-2019 were reviewed. Patients received eradication treatment in case of first ever isolation or new isolation after being infection-free ≥ 1 year. The primary analysis was the comparison of the percentage of successful eradication after receiving IV and non-IV eradication regimens. Demographic and clinical risk factors for eradication failure were also analyzed.

RESULTS: 102 patients with PA isolations and 48 patients with MRSA were analyzed. At one year, 21.6% in PA group and 35.4% in MRSA group were successfully eradicated. There was not any statistically significant difference between IV vs. non-IV antibiotic regimens on eradication in either group. Additionally, none of the clinical risk factors was significantly associated with eradication failure in PA and MRSA groups.

CONCLUSION: In the eradication of PA and MRSA, IV and non-IV treatment regimens did not show any superiority to one another. Non-parenteral eradication could be a better option considering the cost-effectiveness and the treatment burden of IV treatments due to hospitalization and the need for IV access. This article is protected by copyright. All rights reserved.

PMID:34436829 | DOI:10.1002/ppul.25646

J Aerosol Med Pulm Drug Deliv. 2021 Aug 25. doi: 10.1089/jamp.2021.29045.wdb. Online ahead of print.

ABSTRACT

This chapter describes the effects that respiratory disease has on particle deposition in the lungs. The geometry of airways, breathing patterns, and regional ventilation are all affected by various lung diseases, including COPD, asthma, and cystic fibrosis, and in turn modify total and regional deposition from normal. Total particle deposition in the lung is increased by airways obstruction and increased ventilation at rest compared to healthy individuals. Regional particle deposition is 1) shifted from distal to more proximal bronchial airways by airway obstruction, and 2) becomes more heterogeneous due to uneven lung ventilation. The net effect of the changes in total and regional particle deposition from normal is to greatly enhance bronchial airway surface doses for particle deposition while leaving unventilated lung regions inaccessible to the particles. As a result, both therapeutic aerosol delivery and the adverse effects of pollutant particles may be altered with progression of lung disease.

PMID:34435873 | DOI:10.1089/jamp.2021.29045.wdb

J Patient Exp. 2021 Aug 20;8:23743735211034032. doi: 10.1177/23743735211034032. eCollection 2021.

ABSTRACT

There are numerous opportunities for shared decision-making (SDM) in cystic fibrosis (CF) care, yet little is known about patients' SDM experiences. This study evaluated SDM across 159 CF care programs (4024 participants) in the United States. Shared decision-making was assessed using the patient-reported collaboRATE measure, which was included in the CF Foundation's Patient and Family Experience of Care Survey over 18 months. Overall, 69% of respondents reported experiencing SDM. Respondents at pediatric programs were more likely to experience SDM than those at adult programs (72% vs 67%, P < .001). Multivariable logistic regression analyses showed a relationship between SDM and patient age, whereby SDM was less likely to occur with patients aged 18 to 24 years, compared to some younger and older age groups (P = .02-<.001). Shared decision-making was more likely to occur at pediatric programs when patients had better general health (P = .02-<.01), and at pediatric and adult programs when patients had better mental health (P = .02-<.001). Disparities in SDM experiences highlight a need to improve decision-making processes in CF care. Interventions tailored for improving SDM among specific patient populations may be particularly advantageous.

PMID:34435088 | PMC:PMC8381423 | DOI:10.1177/23743735211034032

Biomed Res Int. 2021 Aug 14;2021:6431862. doi: 10.1155/2021/6431862. eCollection 2021.

ABSTRACT

Large quantities of bacteria, including Firmicutes, Actinobacteria, and Bacteroidetes, colonize the surface of the respiratory mucosa of healthy people. They interact and coexist with the local mucosal immune system of the human airway, maintaining the immune stability and balance of the respiratory system. While suffering from chronic respiratory diseases, the microbial population in the airway changes and the proportion of Proteobacteria is increased in patients with asthma. The abundance of the microbial population in patients with chronic obstructive pulmonary disease (COPD) is decreased, and conversely, the proportion of Firmicutes and Proteobacteria increased. The diversity of airway microorganisms in cystic fibrosis (CF) patients is decreased, while pathogenic bacteria and conditional pathogenic bacteria are proliferated in large numbers. The proportion of Firmicutes and Proteobacteria is increased in patients with upper airway cough syndrome (UACS), which replaces the dominance of Streptococcus and Neisseria in the pharynx of a normal population. Therefore, a clear understanding of the immune process of the airway flora and the immune dysfunction of the flora on the pathogenesis of chronic respiratory diseases can provide new ideas for the prevention and treatment of human respiratory diseases.

PMID:34435047 | PMC:PMC8382525 | DOI:10.1155/2021/6431862

MethodsX. 2021 Mar 21;8:101313. doi: 10.1016/j.mex.2021.101313. eCollection 2021.

ABSTRACT

This study develops a comprehensive method to assess seasonal influences on a longitudinal marker and compare estimates between cohorts. The method extends existing approaches by (i) combining a sine-cosine model of seasonality with a specialized covariance function for modeling longitudinal correlation; (ii) performing mediation analysis on a seasonality model. An example dataset and R code are provided. The bundle of methods is referred to as seasonality, mediation and comparison (SMAC). The case study described utilizes lung function as the marker observed on a cystic fibrosis cohort but SMAC can be used to evaluate other markers and in other disease contexts. Key aspects of customization are as follows.•This study introduces a novel seasonality model to fit trajectories of lung function decline and demonstrates how to compare this model to a conventional model in this context.•Steps required for mediation analyses in the seasonality model are shown.•The necessary calculations to compare seasonality models between cohorts, based on estimation coefficients, are derived in the study.

PMID:34434833 | PMC:PMC8374306 | DOI:10.1016/j.mex.2021.101313

Front Pharmacol. 2021 Aug 5;12:518345. doi: 10.3389/fphar.2021.518345. eCollection 2021.

ABSTRACT

Selective phosphodiesterase (PDE) inhibitors are a class of nonsteroid anti-inflammatory drugs for treating chronic inflammatory diseases. Modulation of systemic and airway inflammation is their pivotal mechanism of action. Furthermore, PDE inhibitors modulate cough reflex and inhibit airway mucus secretion. Roflumilast, a selective PDE4 inhibitor, has been extensively studied for the efficacy and safety in chronic obstructive pulmonary disease (COPD) patients. According to the mechanisms of action, the potential roles of PDE inhibitors in treating chronic respiratory diseases including severe asthma, asthma-COPD overlap (ACO), noncystic fibrosis bronchiectasis, and chronic cough are discussed. Since roflumilast inhibits airway eosinophilia and neutrophilia in COPD patients, it reduces COPD exacerbations in the presence of chronic bronchitis in addition to baseline therapies. The clinical studies in asthma patients have shown the comparable efficacy of roflumilast to inhaled corticosteroids for improving lung function. However, the clinical trials of roflumilast in severe asthma have been limited. Although ACO is common and is also associated with poor outcomes, there is no clinical trial regarding its efficacy in patients with ACO despite a promising role in reducing COPD exacerbation. Since mucus hypersecretion is a result of neutrophil secretagogue in patients with chronic bronchitis, experimental studies have shown that PDE4s are regulators of the cystic fibrosis transmembrane conductance regulator (CFTR) in human airway epithelial cells. Besides, goblet cell hyperplasia is associated with an increased expression of PDE. Bronchiectasis and chronic bronchitis are considered neutrophilic airway diseases presenting with mucus hypersecretion. They commonly coexist and thus lead to severe disease. The role of roflumilast in noncystic fibrosis bronchiectasis is under investigation in clinical trials. Lastly, PDE inhibitors have been shown modulating cough from bronchodilation, suppressing transient receptors potential (TRP), and anti-inflammatory properties. Hence, there is the potential role of the drug in the management of unexplained cough. However, clinical trials for examining its antitussive efficacy are pivotal. In conclusion, selective PDE4 inhibitors may be potential treatment options for chronic respiratory diseases apart from COPD due to their promising mechanisms of action.

PMID:34434103 | PMC:PMC8381854 | DOI:10.3389/fphar.2021.518345

BMJ Open Qual. 2021 Aug;10(3):e001529. doi: 10.1136/bmjoq-2021-001529.

ABSTRACT

IntroductionThe Cystic Fibrosis (CF) Foundation chronic care guidelines recommend monitoring spirometry during quarterly multidisciplinary visits to identify early lung function decline. During the COVID-19 pandemic, the CF adult clinic at University of Virginia (UVA) transitioned from the classic CF care model to a model that included quarterly multidisciplinary telemedicine visits. While using telemedicine, CF care needed to include spirometry monitoring. Only a fraction of adult CF patients at UVA owned and used home spirometers (HS) in March 2020.

AIM: The specific aims of this quality improvement (QI) project were to increase the percentage of eligible adult CF patients who owned an HSs from 37% to 85% and to increase the percentage of adult CF patients seen at UVA with available spirometry in telemedicine from 50% to 95% by 31 December 2020.

METHODS: Following the Model for Improvement QI methodology, a standardised process was developed for monitoring forced expiratory volume in 1 s with HS during multidisciplinary telemedicine visits during the COVID-19 pandemic.

INTERVENTION: (1) HSs were distributed to eligible patients and (2) Home spirometry was monitored in eligible patients with each telemedicine visit and results were used for clinical care decisions.

RESULTS: Both specific aims were achieved ahead of expected date. In March 2020, the beginning of the pandemic, 37% (49/131) of patients owned an HS and 50% (9/18) of patients seen via telemedicine performed spirometry at home. By September 2020, 97% (127/131) of adult patients at UVA owned an HS and by October 2020, 96% (24/25) of patients provided spirometry results during their telemedicine encounters.

CONCLUSION: Employing QI tools to standardise the process of monitoring spirometry data with home devices via telemedicine is reliable and sustainable and can be replicated across centres that provide care for patients with CF.

PMID:34433580 | DOI:10.1136/bmjoq-2021-001529

Pediatr Pulmonol. 2021 Aug 25. doi: 10.1002/ppul.25637. Online ahead of print.

NO ABSTRACT

PMID:34432957 | DOI:10.1002/ppul.25637

Curr Opin Pulm Med. 2021 Aug 25. doi: 10.1097/MCP.0000000000000821. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: At many institutions, the Covid-19 pandemic made it necessary to rapidly change the way services are provided to patients, including those with cystic fibrosis (CF). The purpose of this review is to explore the past, present and future of telehealth and virtual monitoring in CF and to highlight certain challenges/considerations in developing such services.

RECENT FINDINGS: The Covid-19 pandemic has proven that telehealth and virtual monitoring are a feasible means for safely providing services to CF patients when traditional care is not possible. However, both telehealth and virtual monitoring can also provide further support in the future in a postcovid era through a hybrid-model incorporating traditional care, remote data collection and sophisticated platforms to manage and share data with CF teams.

SUMMARY: We provide a detailed overview of telehealth and virtual monitoring including examples of how paediatric and adult CF services adapted to the need for rapid change. Such services have proven popular with people with CF meaning that co-design with stakeholders will likely improve systems further. In the future, telehealth and virtual monitoring will become more sophisticated by harnessing increasingly powerful technologies such as artificial intelligence, connected monitoring devices and wearables. In this review, we harmonise definitions and terminologies before highlighting considerations and limitations for the future of telehealth and virtual monitoring in CF.

PMID:34431789 | DOI:10.1097/MCP.0000000000000821

Curr Opin Pulm Med. 2021 Aug 25. doi: 10.1097/MCP.0000000000000816. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Nontuberculous mycobacteria (NTM) are challenging infections among people with cystic fibrosis (pwCF) as the source, modes of transmission, and best practices for diagnosis and treatment are not known. Investigators have defined aspects of NTM infection that are unique to the CF population, as well as features shared with other conditions at risk. This review describes recent advances in our understanding of NTM infection among pwCF.

RECENT FINDINGS: The presence of dominant circulating clones of Mycobacterium abscessus within the CF community worldwide continue to be described, as well as pathogen phenotypes that could evoke greater environmental fitness and infectivity. The risk of direct or indirect transmission between pwCF remains an active focus of investigation, with divergent findings and conclusions reached in a site-specific fashion. Derived largely from studies in non-CF populations, new clinical guidelines are now available. A wide variety of agents are in preclinical development or early phase trials with promising findings, and new therapeutic targets have been identified as our understanding of the complex biology of NTM continues to expand.

SUMMARY: Significant challenges remain in the fight against NTM, however, recent advances in our understanding of the genetics, epidemiology and pathophysiology of pulmonary NTM infection in pwCF are leading efforts to improve clinical care.

PMID:34431787 | DOI:10.1097/MCP.0000000000000816

Neurogastroenterol Motil. 2021 Aug 24:e14224. doi: 10.1111/nmo.14224. Online ahead of print.

ABSTRACT

BACKGROUND: Pediatric cyclic vomiting syndrome (CVS) is a little-known clinical condition, frequently diagnosed with delay. This study aims to describe the clinical presentation and management and to define possible predictive factors of the disease outcome.

METHODS: In this retrospective study, all children who were diagnosed with CVS during the period 2010-2019 in three tertiary academic centers were included. The association between clinical variables and outcomes was investigated.

KEY RESULTS: Fifty-seven children were included (male/female ratio 1.3:1; mean age at diagnosis 8.2 years). At the time of diagnosis, 63% of children had at least one episode every month. One or more prodromes were reported by 75% of patients. Family history of migraine was reported for 47% of children. Nearly, all of the children were started on prophylactic treatment. The median follow-up period was 29 months ± 15. Overall, 56% of children had resolution of vomiting. Twenty-six percent of children developed migraine. There were no differences in gender, age at onset, duration of follow-up, severity, medication, family history, or trigger factors between children who underwent resolution of vomiting and those who did not, or between children who suffered from migraine or not at follow-up. Four types of disease outcome were recognized, that is, resolution of vomiting with or without associated symptoms; persistence of vomiting with or without associated symptoms.

CONCLUSIONS AND INFERENCES: Cyclic vomiting syndrome clinical presentation has inter-individual variability. Most children recover at follow-up, but often develop further somatic symptoms. In this study, no clinical variable clearly predicted the evolution of the syndrome toward one or the other outcome.

PMID:34431167 | DOI:10.1111/nmo.14224

Hepatol Commun. 2021 May 13;5(8):1362-1372. doi: 10.1002/hep4.1719. eCollection 2021 Aug.

ABSTRACT

Methods to identify children with cystic fibrosis (CF) at risk for development of advanced liver disease are lacking. We aim to determine the association between liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) with research ultrasound (US) patterns and conventional hepatic markers as a potential means to follow liver disease progression in children with CF. ELASTIC (Longitudinal Assessment of Transient Elastography in CF) is a nested cohort of 141 patients, ages 7-21, enrolled in the Prediction by US of Risk of Hepatic Cirrhosis in CF (PUSH) Study. We studied the association between LSM with research-grade US patterns (normal [NL], heterogeneous [HTG], homogeneous [HMG], or nodular [NOD]) and conventional hepatic markers. In a subgroup (n = 79), the association between controlled attenuation parameter (CAP) and US pattern was explored. Among 133 subjects undergoing VCTE, NOD participants (n = 26) had a significantly higher median (interquartile range) LSM of 9.1 kPa (6.3, 15.8) versus NL (n = 72, 5.1 kPa [4.2, 7.0]; P < 0.0001), HMG (n = 17, 5.9 kPa [5.2, 7.8]; P = 0.0013), and HTG (n = 18, 6.1 kPa [4.7, 7.0]; P = 0.0008) participants. HMG participants (n = 14) had a significantly higher mean CAP (SD) (270.5 dB/m [61.1]) compared with NL (n = 40, 218.8 dB/m [46.5]; P = 0.0027), HTG (n = 10, 218.1 dB/m [60.7]; P = 0.044), and NOD (n = 15, 222.7 dB/m [56.4]; P = 0.041) participants. LSM had a negative correlation with platelet count (rs = - 0.28, P = 0.0071) and positive correlation with aspartate aminotransferase-to-platelet ratio index (rs = 0.38, P = 0.0002), Fibrosis-4 index (rs = 0.36, P = 0.0007), gamma-glutamyltransferase (GGT; rs = 0.35, P = 0.0017), GGT-to-platelet ratio (rs = 0.35, P = 0.003), and US spleen size z-score (rs = 0.27, P = 0.0073). Conclusion: VCTE is associated with US patterns and conventional markers in patients with liver disease with CF.

PMID:34430781 | PMC:PMC8369935 | DOI:10.1002/hep4.1719

MethodsX. 2021 Jun 18;8:101419. doi: 10.1016/j.mex.2021.101419. eCollection 2021.

ABSTRACT

Successful use of the CRISPR-Cas9 system for gene manipulation relies on identifying effective and efficient guide RNA sequences (gRNAs). When the goal is to create transgenic animal/rodent models by knocking-in desired sequences using homology-directed repair (HDR), selecting effective guides becomes even more critical to minimize developmental time and resources. Currently, validation experiments for gRNAs for generating rat models are carried out using immortalized rat cells. However, there are several limitations with using such cell lines, including ploidy of the genome, non-predictive transfection efficiency, and the ability to identify gene modifications efficiently within diverse cell populations. Since embryos are authentic representatives of live animals compared to cell lines, validating CRISPR guides for their nuclease activity in freshly isolated embryos will provide greater accuracy of in vivo gene editing efficiency. In contrast to microinjections, delivery by electroporation is a more accessible method that can be simple and does not require special skills and equipment. We demonstrate an accessible workflow to either delete or edit target genes in vivo in rats using the efficient editing of a human mutation in alpha7 nicotinic acetylcholine receptor subunit (CHRNA7) ortholog using electroporation as a delivery method for CRISPR-Cas9 ribonucleoprotein complexes in rat embryos.•Upon identifying CRISPR targets at the desired genetic alteration site, we designed homologydriven repair (HDR) templates for effective and easy identification of gene editing by Restriction Fragment Length Polymorphism (RFLP).•Cultured rat embryos can be genotyped to assess CRISPR activity as seen by either presence of indels resulting from NHEJ or knock-in of repair template resulting from homology driven repair.•Heteroduplex mobility assay (HMA) and Restriction Fragment Length Polymorphism (RFLP) of PCR products can be performed reliably and reproducibly at a low-cost.

PMID:34430314 | PMC:PMC8374522 | DOI:10.1016/j.mex.2021.101419

Pediatr Pulmonol. 2021 Aug 24. doi: 10.1002/ppul.25641. Online ahead of print.

ABSTRACT

BACKGROUND: ABPA complicating Cystic Fibrosis is frequently associated with significant structural lung damage as assessed by CT scanning.

METHODS: Using a validated CF scoring system (SLD score) we examined the degree of structural lung disease in a group of 25 children with CF who had received steroid therapy for ABPA (CF-ABPA) and compared our findings to a matched group of CF patients without ABPA (CF-CON) using both cross section and longitudinal analysis. Further, we examined the structure function correlation between CT findings and lung function.

RESULTS: Mean SLD score (expressed as a percentage of maximal score) was significantly higher (worse) in the CF-ABPA group than the CF-CON group (29.3% CF-ABPA vs 18.7 % CF-CON p<0.05). CF-ABPA patients showed significantly greater rate of development of structural lung disease over time than CF-CON patients (6.8% per year vs 1.4% p<0.01). We found no correlation between lung function and the degree of structural lung disease.

CONCLUSIONS: ABPA in children with CF is associated with significantly more structural lung disease than that found in children with CF without ABPA. Despite interventive steroid therapy lung disease progresses more rapidly in those patients with ABPA and CF than control patients with CF. This article is protected by copyright. All rights reserved.

PMID:34427991 | DOI:10.1002/ppul.25641

Biomed Pharmacother. 2021 Aug 21;142:112030. doi: 10.1016/j.biopha.2021.112030. Online ahead of print.

ABSTRACT

Oriental herbal medicine with the two bioactive constituents, β-eudesmol (BE) and atractylodin (AT), has been used as a remedy for gastrointestinal disorders. There was no scientific evidence reporting their antidiarrheal effect and underpinning mechanisms. Therefore, we aimed to investigate the anti-secretory activity of these two compounds in vitro. The inhibitory effect of BE and AT on cAMP-induced Cl- secretion was evaluated by Ussing chamber in human intestinal epithelial (T84) cells. Short-circuit current (ISC) and apical Cl- current (ICl-) were measured after adding indirect and direct cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel activator. MTT assay was used to determine cellular cytotoxicity. Protein-ligand interaction was investigated by in silico molecular docking analysis. BE, but not AT concentration-dependently (IC50 of ~1.05 µM) reduced cAMP-mediated, CFTRinh-172 inhibitable Cl- secretion as determined by transepithelial ISC across a monolayer of T84 cells. Potency of CFTR-mediated ICl- inhibition by BE did not change with the use of different CFTR activators suggesting a direct blockage of the channel active site(s). Pretreatment with BE completely prevented cAMP-induced ICl-. Furthermore, BE at concentrations up to 200 µM (24 h) had no effect on T84 cell viability. In silico studies indicated that BE could best dock onto dephosphorylated structure of CFTR at ATP-binding pockets in nucleotide-binding domain (NBD) 2 region. These findings provide the first evidence for the anti-secretory effect of BE involving inhibition of CFTR function. BE represents a promising candidate for the therapeutic or prophylactic intervention of diarrhea resulted from intestinal hypersecretion of Cl.

PMID:34426253 | DOI:10.1016/j.biopha.2021.112030

Nurse Pract. 2021 Sep 1;46(9):48-55. doi: 10.1097/01.NPR.0000769756.82495.f3.

ABSTRACT

Cystic fibrosis is an autosomal recessive genetic disorder that causes a lifetime of debilitating and potentially fatal complications affecting the lungs and other organ systems. Over 1,700 gene mutations that cause this rare disorder have been identified. This article describes the current treatment landscape for adults with CF, including the 2019 FDA approval of a breakthrough triple-drug combination therapy that may significantly improve the quality of life for an estimated 90% of patients with CF.

PMID:34424887 | DOI:10.1097/01.NPR.0000769756.82495.f3

Cochrane Database Syst Rev. 2021 Aug 23;8:CD008901. doi: 10.1002/14651858.CD008901.pub5.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is an inherited condition causing disease most noticeably in the lungs, digestive tract and pancreas. People with CF often have malnutrition and growth delay. Adequate nutritional supplementation does not improve growth optimally and hence an anabolic agent, recombinant human growth hormone (rhGH), has been proposed as a potential intervention. This is an update of a previously published review.

OBJECTIVES: To evaluate the effectiveness and safety of rhGH therapy in improving lung function, quality of life and clinical status of children and young adults with CF.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 12 January 2021. We also searched ongoing trials registers: clinicaltrials.gov from the United States - date of latest search 19 Jun 2021; WHO International Clinical Trials Registry Platform (ICTRP) - date of latest search 05 March 2018 (not available in 2021). We conducted a search of relevant endocrine journals and proceedings of the Endocrinology Society meetings using Web of Science, Scopus and Proceedings First. Date of latest search: 21 Jun 2021. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of all preparations of rhGH compared to either no treatment, or placebo, or each other at any dose (high-dose and low-dose) or route and for any duration, in children or young adults (aged up to 25 years) diagnosed with CF (by sweat test or genetic testing).

DATA COLLECTION AND ANALYSIS: Two authors independently screened papers, extracted trial details and assessed their risk of bias. We assessed the quality of the evidence using the GRADE system.

MAIN RESULTS: We included eight trials (291 participants, aged between five and 23 years) in the current version of the review. Seven trials compared standard-dose rhGH (approximately 0.3 mg/kg/week) to no treatment and one three-arm trial (63 participants) compared placebo, standard-dose rhGH (0.3 mg/kg/week) and high-dose rhGH (0.5 mg/kg/week). Six trials lasted for one year and two trials for six months. We found that rhGH treatment may improve some of the pulmonary function outcomes, but there was no difference between standard and high-dose levels (low-certainty evidence, limited by inconsistency across the trials, small number of participants and short duration of therapy). The trials show evidence of improvement in the anthropometric parameters (height, weight and lean body mass) with rhGH therapy, again no differences between dose levels. We found improvement in height for all comparisons (very low- to low-certainty evidence), but improvements in weight and lean body mass were only reported for standard-dose rhGH versus no treatment (very low-certainty evidence). There is some evidence indicating a change in the level of fasting blood glucose with rhGH therapy, however, it did not cross the clinical threshold for diagnosis of diabetes in the trials of short duration (low-certainty evidence). There is low- to very low-certainty evidence for improvement of pulmonary exacerbations with no further significant adverse effects, but this is limited by the short duration of trials and the small number of participants. One small trial provided inconsistent evidence on improvement in quality of life (very low-certainty evidence). There is limited evidence from three trials in improvements in exercise capacity (low-certainty evidence). None of the trials have systematically compared the expense of therapy on overall healthcare costs.

AUTHORS' CONCLUSIONS: When compared with no treatment, rhGH therapy is effective in improving the intermediate outcomes in height, weight and lean body mass. Some measures of pulmonary function showed moderate improvement, but no consistent benefit was seen across all trials. The significant change in blood glucose levels, although not causing diabetes, emphasizes the need for careful monitoring of this adverse effect with therapy in a population predisposed to CF-related diabetes. No significant changes in quality of life, clinical status or side-effects were observed in this review due to the small number of participants. Long-term, well-designed randomised controlled trials of rhGH in individuals with CF are required prior to routine clinical use of rhGH in CF.

PMID:34424546 | DOI:10.1002/14651858.CD008901.pub5